Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

Gao Zhang, Dennie T. Frederick, Lawrence Wu, Zhi Wei, Clemens Krepler, Satish Srinivasan, Young Chan Chae, Xiaowei Xu, Harry Choi, Elaida Dimwamwa, Omotayo Ope, Batool Shannan, Devraj Basu, Dongmei Zhang, Manti Guha, Min Xiao, Sergio Randell, Katrin Sproesser, Wei Xu, Jephrey Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Tara C. Gangadhar, Ravi K. Amaravadi, Mengnan Gu, Caiyue Xu, Abheek Ghosh, Weiting Xu, Tian Tian, Jie Zhang, Shijie Zha, Qin Liu, Patricia Brafford, Ashani Weeraratna, Michael A. Davies, Jennifer A. Wargo, Narayan G. Avadhani, Yiling Lu, Gordon B. Mills, Dario C. Altieri, Keith T. Flaherty, Meenhard Herlyn

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.